Metabolic Pathways May Lead Researchers to Novel Therapeutic Targets in Neuro-Oncology

Shannon Connelly
Published Online: Monday, Dec 26, 2016

I hope to see, and I think we will see, whole new strategies based on developing drugs against these novel metabolic targets and in fact, possibly even diet modifications. There has been a lot over the last 10 or 20 years about special kind of diets, like ketogenic diets, that effectively target metabolism. I know they haven’t been studied well, they haven’t necessarily been done in the correct way—they haven’t been done in conjunction with pharmacologic intervention. I think we’re going to see those types of strategies. I know we will, because we’re doing those types of strategies at our center and in other centers, and I think it’s a great unexplored and an exciting old/new area.

What are the effects of stress on the tumor metabolic environment?

We know that stress causes hormonal changes and hormonal changes are involved in metabolism. For instance, we know that stress induces glucocorticoids and causes adrenal hyperactivity. When you get high levels of adrenocorticotropic hormone (ACTH) and steroids, you increase insulin levels. We know that insulin drives tumor growth and tumor promotion. Although there’s no data, one could speculate that high levels of stress hormones over long periods of time may increase insulin, and may increase your chances of type 2 diabetes, which has been shown, and we think that high levels of insulin resistance, hypoglycemia, certainly can help fuel tumor metabolism.

Does age play a factor in metabolic pathways?

The answer is we don’t know, but I’m sure that it does. We know that for instance in a normal aging brain, metabolism is dramatically different than it is in developing in a middle-aged brain. That is well established and there’s an increasing number of papers being published looking at the molecular mechanism of that. If the normal surrounding brain metabolism is different, tumors don’t live in isolation, they live within the host, so I’m sure the metabolic profile and the details of the metabolism of tumors in an older versus a younger brain is quite different, but I think we are just beginning to explore those aspects.

Are there any ongoing trials that you are currently watching with interest?

Certainly, there is a whole series and it’s a big focus on a whole new series of drugs that target this mutant IDH gene, so these IDH inhibitors are being explored now both in low-grade and high-grade gliomas with variable success. I think we’re just beginning to learn to use those.

Centers like ours are looking at the old kitogenic diet in combination with very specific new pharmacologic interventions like PI3 kinase inhibitors and mTOR inhibitors as a way of trying to hit the metabolism in various fronts of tumors. Those kinds of trials and therapeutic interventions are just beginning to be seen.

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